EXPERT COMMENTARY

Silvio E. Inzucchi MD, comments on SAVOR-TIMI 53

“Reassurance of the Overall Cardiovascular Safety of Saxagliptin and, One Might Infer, Other DPP-4 Inhibitors—But Heart Failure Signal Needs to Be Explored Further”

Antihyperglycemic therapy for type 2 diabetes has evolved significantly over the past decade-and-a-half. Incretin-based therapies—the GLP-1 receptor agonists (RAs) and DPP-4 inhibitors—are increasingly popular. The DPP-4 inhibitors are now widely used, mainly because of their perceived safety and the fact that they are generally well tolerated by patients.1 Although one of the mechanisms of action of DPP-4 inhibitors is to increase pancreatic insulin secretion, this occurs in a glucose-dependent fashion, minimizing the risk of hypoglycemia.2

Both incretin-based classes have the potential for cardiovascular benefit. GLP-1 receptors in the heart may mediate cardioprotective actions, and DPP-4 inhibition may increase the circulating numbers of bone-marrow derived stem cells that repair injured vascular endothelial cells.3

For these reasons and to respond to the FDA’s recent guidance to industry concerning cardiovascular safety of new diabetes medicines, several GLP-1 RAs and DPP-4 inhibitors are being assessed in large cardiovascular studies.

The first of these to report is SAVOR-TIMI 53, which assessed the cardiovascular safety and efficacy of saxagliptin compared with placebo in more than 16,000 patients with type 2 diabetes and a history of or risk factors for cardiovascular events.4 Mean follow-up was slightly more than 2 years. A1c was, on average 0.3% lower in the group randomized to saxagliptin which, along with placebo, was used in conjunction with other antihyperglycemic therapies.

The primary endpoint, a composite of cardiovascular death, myocardial infarction, or ischemic stroke, occurred equally between the two groups (HR=1.00, 95% CI, 0.89-1.12; P=0.99 for inferiority; P<0.001 for noninferiority). The same applied to a variety of other cardiovascular secondary endpoints, with the exception of heart failure hospitalization, which was more frequent in the saxagliptin group (3.5% vs. 2.8%; HR=1.27 [1.07-1.51]).

Based on recent concerns regarding pancreatic effects of incretin therapies, two safety endpoints, pancreatitis and pancreatic cancer, were studied and found to be statistically equivalent between the two groups. Actually, there were numerically more pancreatic cancers diagnosed in placebo-treated patients (12 vs 5; P=0.095).

Aside from the unexpected heart failure signal, SAVOR-TIMI 53 provides reassurance of the overall cardiovascular safety of this, and, one might infer, other DPP-4 inhibitors. The trial may be viewed by some as disappointing, however given emerging preclinical evidence that suggested potential cardiovascular benefit5, combined with several meta-analyses of Phase III trials involving several drugs of this class that were more encouraging6-8.

Perhaps it was overly optimistic to expect benefits to accrue after such a short period of time, however. Nonetheless, the lack of even a trend in the direction of reduced cardiovascular events bodes poorly for other drugs of this class. That is, they, too, are unlikely to show a cardiovascular benefit given their shared mechanism of action.

Two additional comments are warranted. The heart failure signal needs to be explored further. I can’t conceive of a biological explanation for this finding, and it may result merely from chance alone. Nonetheless, GLP-1 receptors are found in the heart, and since DPP-4 inhibition leads to increase circulating concentrations of this incretin hormone in the postprandial setting, further inquiry is necessary. It will be interesting to see if any such trend emerges from the other DPP-4 inhibitor trials. As for the issue concerning pancreatic safety, the data from SAVOR-TIMI 53 are encouraging, but we will need to await the other similar trials to report—from both DPP-4 inhibitors and the GLP-1 RAs—before we fully understand the potential pancreatic risk associated with incretin-based therapy.

Silvio E. Inzucchi, MD, is Professor of Medicine (Endocrinology); Clinical Director, Section of Endocrinology; and Director, Yale Diabetes Center at Yale University School of Medicine in New Haven, Connecticut.

Dr Inzucchi is an advisor to Merck and Co., Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim, and Bristol-Myers Squibb Company. He is a member of the Data Safety Monitoring Board/Data Review Committees for Novo Nordisk, Inc. and Gilead Sciences, Inc.

The pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States.

September 2013

This content was not associated with funding via an educational grant or a promotional/commercial interest.